Short oral regimens for pulmonary rifampicin-resistant tuberculosis (TB-PRACTECAL): an open-label, randomised, controlled, phase 2B-3, multi-arm, multicentre, non-inferiority trial
Authors: Bern-Thomas Nyang'wa, Catherine Berry, Emil Kazounis, Ilaria Motta, Nargiza Parpieva, Zinaida Tigay, Ronelle Moodliar, Matthew Dodd, Varvara Solodovnikova, Irina Liverko, Shakira Rajaram, Mohammed Rassool, Timothy McHugh, Melvin Spigelman, David A Moore, Koert Ritmeijer, Philipp du Cros, Katherine Fielding, Erin Da Costa, Nathalie Lachenal, Nicola James, Animesh Sinha, Kristen LeBeau, Emma Douch, Pascal Jolivert, Hannah Poulsom, Marion Conijn, Sean King, Hannah Spencer, Emma Cunden, Charlotte Batts, Thuy Vuong, Sebastian Dietrich, Melissa McRae, Sidney Wong, Eugene Sun, Morounfolu Olugbosi, Leslie Shanks, Michael Hughes, Payam Nahid, Johnstone Kumwenda, Todd Lorenz, Suman Majumdar, Robert C. Horsburgh, Eric Nuermberger, Graeme Meintjes, Kathleen Eisenach, Christian Lienhardt, Andrew Nunn, Christoph Lange, Laura Park, Charlotte Gatts, Dominic Warren, Robert Kleiman, George Mokua Nyangweso, Michael Ochieng, Thaddaeus Egondi, Kevin Onyango, Truphoso Omollo, Raymond Omollo, Jo Sturgess, Steven Saunders,, Elizabeth Allen, Suzanne Gajewski,, Valentina Butoescu, Jarmila Hanekova, Coralie Etter, Yerkbulan Kambarov, Siza Mphele, Victoria Sukhinina, Olesya Huzar, Andrey Reshetnikov, Christine Cilliè, Nada Ahmed, Robert Hunt, Corinne Merle, Allanazarova Gulayim, Mansa Mbenga, Zlikha Saparbaevna Baltasheva, Tleubergen Abdrasuliev, Hasmik Margaryan, Utemuratova Gozzal Urgenishbaevna, Alena Skrahina, Natalia Yatskevich, Dzmitry Viatushka, Tatsiana Apanasevich, Aliaksandr Skrahin, Lynette Duckworth, Cindy Narasimooloo, Ndlovu Ellah Lesego, Sharon Motlhako, Mamomoko Ephenia Mashamaite, Evelyn Mojapelo
Journal: The Lancet Respiratory Medicine (2023)

BackgroundAround 500 000 people worldwide develop rifampicin-resistant tuberculosis each year. The proportion of successful treatment outcomes remains low and new treatments are needed. Following an interim analysis, we report the final safety and efficacy outcomes of the TB-PRACTECAL trial, evaluating the safety and efficacy of oral regimens for the treatment of rifampicin-resistant tuberculosis.MethodsThis open-label, randomised, controlled, multi-arm, multicentre, non-inferiority trial was conducted at seven hospital and community sites in Uzbekistan, Belarus, and South Africa, and enrolled participants aged 15 years and older with pulmonary rifampicin-resistant tuberculosis. Participants were randomly assigned, in a 1:1:1:1 ratio using variable block randomisation and stratified by trial site, to receive 36–80 week standard care; 24-week oral bedaquiline, pretomanid, and linezolid (BPaL); BPaL plus clofazimine (BPaLC); or BPaL plus moxifloxacin (BPaLM) in stage one of the trial, and in a 1:1 ratio to receive standard care or BPaLM in stage two of the trial, the results of which are described here. Laboratory staff and trial sponsors were masked to group assignment and outcomes were assessed by unmasked investigators. The primary outcome was the percentage of participants with a composite unfavourable outcome (treatment failure, death, treatment discontinuation, disease recurrence, or loss to follow-up) at 72 weeks after randomisation in the modified intention-to-treat population (all participants with rifampicin-resistant disease who received at least one dose of study medication) and the per-protocol population (a subset of the modified intention-to-treat population excluding participants who did not complete a protocol-adherent course of treatment (other than because of treatment failure or death) and those who discontinued treatment early because they violated at least one of the inclusion or exclusion criteria). Safety was measured in the safety population. The non-inferiority margin was 12%. This trial is registered with ClinicalTrials.gov, NCT02589782, and is complete.FindingsBetween Jan 16, 2017, and March 18, 2021, 680 patients were screened for eligibility, of whom 552 were enrolled and randomly assigned (152 to the standard care group, 151 to the BPaLM group, 126 to the BPaLC group, and 123 to the BPaL group). The standard care and BPaLM groups proceeded to stage two and are reported here, post-hoc analyses of the BPaLC and BPaL groups are also reported. 151 participants in the BPaLM group and 151 in the standard care group were included in the safety population, with 138 in the BPaLM group and 137 in the standard care group in the modified intention-to-treat population. In the modified intention-to-treat population, unfavourable outcomes were reported in 16 (12%) of 137 participants for whom outcome was assessable in the BPaLM group and 56 (41%) of 137 participants in the standard care group (risk difference −29·2 percentage points [96·6% CI −39·8 to −18·6]; non-inferiority and superiority p<0·0001). 34 (23%) of 151 participants receiving BPaLM had adverse events of grade 3 or higher or serious adverse events, compared with 72 (48%) of 151 participants receiving standard care (risk difference −25·2 percentage points [96·6% CI −36·4 to −13·9]). Five deaths were reported in the standard care group by week 72, of which one (COVID-19 pneumonia) was unrelated to treatment and four (acute pancreatitis, suicide, sudden death, and sudden cardiac death) were judged to be treatment-related.InterpretationThe 24-week, all-oral BPaLM regimen is safe and efficacious for the treatment of pulmonary rifampicin-resistant tuberculosis, and was added to the WHO guidance for treatment of this condition in 2022. These findings will be key to BPaLM becoming the preferred regimen for adolescents and adults with pulmonary rifampicin-resistant tuberculosis.FundingMédecins Sans Frontières.